Anti-inflammatory exosomes mediate the beneficial effect of mesenchymal stem cell therapy on lung preservation

Abstract

Background & Aim Mesenchymal stem cell (MSCs) therapy protects donor lungs against ischemic-reperfusion injury. We recently reported that local infusion of human umbilical cord-derived MSCs during donor lung ablation significantly conserved lung function. The anti-inflammatory effect of MSCs is mainly exerted through a paracrine mechanism. Thus, in the present study, we investigated whether the preservation capacity of MSCs is related to the secretion of anti-inflammatory exosomes. Methods, Results & Conclusion The rat lung preservation model settled before consisted on: cardiac arrest, warm ischemia (2h) in which cells were administered at 1h via the pulmonary artery (1 × 10^6 cells or vehicle), cold ischemia, and normothermic ex-vivo lung perfusion with ventilation. Here, we assessed 3 experimental groups right after the warm ischemia period (2h): vehicle, MSCs, and exosomes (released by 1 × 10^6 cells). Exosomes were chromatographically purified from MSCs conditioned medium and their anti-inflammatory activity was evaluated, in vitro, based on their ability to suppress the acquisition of M1 phenotype in LPS-stimulated RAW264.7 cells. Physiologic data (pressure-volume curves) were acquired right after the cardiac arrest and at the end of the warm ischemia time and lung biopsies were taken to study edema formation, neutrophil infiltration, redox profile, and inflammatory molecular markers. As expected, exosomes were positive for human-specific CD63 and CD81, and showed the tipical size and morphology by electron microscopy. Exosomes also exposed their anti-inflammatory activity by significantly reducing IL-6 secretion in LPS-stimulated macrophages by 60%. Previously, in the complete lung preservation model (4.5h), we observed that MSCs administration facilitated organ preservation by significantly reducing the drop on lung compliance (∼50% vs vehicle treated group, p Taking in consideration our previous data and these new results we conclude that MSCs-derived exosomes have a key role in lung preservation mediated by MSCs. Consequently, we postulate that exosomes may represent an innovative cell free therapy for organ preservation.